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Repeated doses administration of MDMA in humans: pharmacological effects and pharmacokinetics

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Abstract

Rationale

3,4-Methylenedioxymethamphetamine (MDMA, “ecstasy”) is increasingly used by young people for its euphoric and empathic effects. MDMA presents non-linear pharmacokinetics, probably by inhibition of cytochrome P450 isoform 2D6. Users are known to often take more than one dose per session. This practice could have serious implications for the toxicity of MDMA.

Objective

To evaluate the pharmacological effects and pharmacokinetics of MDMA following the administration of two repeated doses of MDMA (24 h apart).

Methods

A randomised, double-blind, cross-over, placebo controlled trial was conducted in nine healthy male subjects. Variables included physiological, psychomotor performance, subjective effects, endocrine response and pharmacokinetics. MDMA 100 mg or placebo was administered in two successive doses separated by an interval of 24 h.

Results

MDMA produced the prototypical effects of the drug. Following a second dose, plasma concentrations of MDMA increased (AUC 77% and Cmax 29%) in comparison with the first. The increase is greater than those expected by simple accumulation and indicates metabolic inhibition. The pharmacological effects after the second dose were slightly higher than those observed after the first in the majority of variables including blood pressure, heart rate, most subjective effects and cortisol concentrations. The effects were similar in the case of pupil diameter, esophoria and prolactin.

Conclusions

Pharmacological effects after the second administration were higher than those following the first but lower than expected. A disproportionate increase in plasma concentrations in MDMA and MDA was observed most likely due to metabolic inhibition. This inhibition lasts at least 24 h. Further experiments need to be conducted to evaluate its duration.

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Acknowledgements

This study was supported in part by grants from Generalitat de Catalunya (2001SGR00407), Fondo de Investigacíon Sanitaria (98/0181 and 01/1336). We are indebted to Esther Menoyo and Isabel Sánchez for their valuable assistance throughout the clinical trial. The clinical trial conformed to the derivates of Spanish laws concerning clinical trials (Ley de Medicamiento 25/1990, Real Decreto 561/1993).

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Authors and Affiliations

  1. Pharmacology Unit, Institut Municipal d’Investigació Mèdica (IMIM), Doctor Aiguader 80, 08003, Barcelona, Spain

    M. Farré, R. de la Torre, B. Ó Mathúna, P. N. Roset, A. M. Peiró, J. Ortuño, M. Pujadas & J. Camí

  2. Universitat Autònoma, Barcelona, Spain

    M. Farré, R. de la Torre, P. N. Roset & M. Torrens

  3. Universitat Pompeu Fabra, Barcelona, Spain

    R. de la Torre, B. Ó Mathúna & J. Camí

  4. IAPS-Hospital del Mar, Barcelona, Spain

    R. de la Torre & M. Torrens

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  1. M. Farré
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Correspondence to M. Farré.

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Farré, M., de la Torre, R., Ó Mathúna, B. et al. Repeated doses administration of MDMA in humans: pharmacological effects and pharmacokinetics. Psychopharmacology 173, 364–375 (2004). https://doi.org/10.1007/s00213-004-1789-7

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  • DOI: https://doi.org/10.1007/s00213-004-1789-7

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